CLINICAL REPORT ... · ectopia lentis or skeletal manifestations alone, may be the only pre-senting signs. Mutations in FBN1 are found in up to 95% of those meeting diagnostic criteria.3,4

CLINICAL REPORT

Health Supervision for Children With Marfan Syndrome

abstractMarfan syndrome is a systemic, heritable connective tissue disorderthat affects many different organ systems and is best managed by us-ing a multidisciplinary approach. The guidance in this report isdesigned to assist the pediatrician in recognizing the features of Mar-fan syndrome as well as caring for the individual with this disorder.Pediatrics 2013;132:e1059–e1072

INTRODUCTION

Marfan syndrome is a heritable, multisystem disorder of connectivetissue with extensive clinical variability. It is a relatively commoncondition, with approximately 1 in 5000 people affected.1 Cardinalfeatures involve the ocular, musculoskeletal, and cardiovascularsystems. Because of the high degree of variability of this disorder,many of these clinical features can be present at birth or can man-ifest later in childhood or even adulthood.

Marfan syndrome is an autosomal dominant disorder mainly caused bydefects in FBN1, the gene that codes for the protein fibrillin, althoughpatients with mutations in other genes, including TGFBR1 and TGFBR2,have also been reported, albeit rarely.2 Mutations in FBN1 are asso-ciated with a wide phenotypic spectrum ranging from classic featuresof Marfan syndrome presenting in childhood and early adulthood tosevere neonatal presentation with rapidly progressive disease. At theother end of the spectrum, isolated phenotypic features, such asectopia lentis or skeletal manifestations alone, may be the only pre-senting signs. Mutations in FBN1 are found in up to 95% of thosemeeting diagnostic criteria.3,4 However, the diagnosis of Marfan syn-drome is clinically based on well-defined criteria (revised Ghent di-agnostic criteria [Tables 1 and 2]) and does not include the wholespectrum of FBN1-related disorders, especially the milder, isolatedfeatures.5 Thus, genetic testing of FBN1 is best reserved for thosepatients in whom there is a strong clinical suspicion of Marfan syn-drome, including those with the “emerging” phenotype, using estab-lished guidelines of the interpretation of such results. Because manyof the more specific clinical features are age dependent (eg, ectopialentis, aortic dilation, dural ectasia, protrusio acetabuli), children andadolescents may not fulfill formal diagnostic criteria and are oftendescribed as having “potential” Marfan syndrome. Younger patients atrisk for Marfan syndrome on the basis of clinical features or a posi-tive family history should be evaluated periodically (eg, at 5, 10, 15,and 18 years of age) in lieu of genetic testing.

Brad T. Tinkle, MD, PhD, Howard M. Saal, MD, and theCOMMITTEE ON GENETICS

KEY WORDMarfan syndrome

This document is copyrighted and is property of the AmericanAcademy of Pediatrics and its Board of Directors. All authorshave filed conflict of interest statements with the AmericanAcademy of Pediatrics. Any conflicts have been resolved througha process approved by the Board of Directors. The AmericanAcademy of Pediatrics has neither solicited nor accepted anycommercial involvement in the development of the content ofthis publication.

The guidance in this report does not indicate an exclusivecourse of treatment or serve as a standard of medical care.Variations, taking into account individual circumstances, may beappropriate.

www.pediatrics.org/cgi/doi/10.1542/peds.2013-2063

doi:10.1542/peds.2013-2063

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PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

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Many features of Marfan syndrome areseen in isolation as well as in othergenetic syndromes (Table 3).6 Di-agnosis should be clearly establishedwhen possible. For those suspected tohave Marfan syndrome based onclinical grounds after physical, car-diac, and ophthalmic evaluation butwho may not meet full clinical criteria,one can consider FBN1 testing.7

Approximately one-quarter of casesoccur as a result of a new mutation,with the remainder inherited from anaffected parent. Because of the broadphenotypic variability, some parentswill not be readily recognized as hav-ing Marfan syndrome.8 In such cases,both parents and at-risk first-degreerelatives should have physical, oph-thalmologic, and cardiac evaluation aswell, with consideration of genetictesting.

GROWTH AND DEVELOPMENT

Overall growth is characterized byexcessive linear growth of the longbones. Typically, most individuals withMarfan syndrome are tall for age(Figs 1 and 2), but it is important tonote that not all affected individualsare tall by population standards; theyare typically taller than predicted fortheir family (excluding others withMarfan syndrome).9 Mean final heightwas 191.3 ± 9 cm (75 in) for Q:3malesand 175.4 ± 8.2 cm (69 in) forfemales.

The growth of the tubular bones isaccelerated in Marfan syndrome,resulting in disproportionate features.The extremities are often dispropor-tionately long in comparison with thetrunk (dolichostenomelia), altering theupper-to-lower segment and the arm-span-to-height ratios. The arm-span-to-height ratio is relatively fixed duringchildhood, but the upper-to-lowersegment ratio changes during growth(Fig 3). Use of such measurementsshould take into account racial, gender,and age differences. Similarly, the tu-bular bones of the hand and fingersare elongated, but the palm is notproportionately wider, resulting in rel-ative arachnodactyly as measured bythe thumb and wrist signs (Fig 4).

Excessive growth in Marfan syndromeis attributable, in part, to a peakgrowth velocity that typically occurs asmuch as 2 years earlier than the

general population.9 Hormonal ther-apy to limit adult height is rarely usedin males. Complications can includeaccelerated growth, early puberty,and the undesirable consequences ofassociated increased blood pressure,which may increase the progressionof the aortic dilation. Prepubertalfemales have been treated with high-dose estrogen therapy and pro-gesterone to reduce final adult heightin the past; however, this treatmentremains controversial in both itspsychosocial and medical benefits.10

Lean muscle mass is also affected.Individuals with Marfan syndrome of-ten show a paucity of muscle mass andfat stores despite adequate caloricintake. Weight is often below the 50thpercentile for age.9

Cognitive ability in patients with Marfansyndrome is usually within the typicalrange for the general population. How-ever, poor vision and underlying medicalproblems may interfere with learning.Similarly, many patients report chronicfatigue, which may affect educationand can manifest as inattention orpoor concentration.11 The etiology ofthe fatigue is likely heterogeneous,in part because of the underlyingchronic condition, medications suchas β-blockers, sleep disturbance (eg,sleep apnea), and/or orthostatic in-tolerance.12

SKELETAL

Skeletal system involvement in Marfansyndrome is characterized by boneovergrowth. Such overgrowth may benoticeable at birth or can develop inyoung children, with a tendency toprogress more rapidly during periodsof rapid growth, necessitating closemonitoring at such times (Table 4).

Overgrowth of the ribs can push thesternum inward (pectus excavatum)or outward (pectus carinatum). Nearlytwo-thirds of patients with Marfan

TABLE 1 Revised Ghent Diagnostic Criteriafor Marfan Syndrome

Diagnosis of definitive Marfan syndrome(any of the following)• Aortic root ≥2 z score and ectopia lentis• Aortic root ≥2 z score and FBN1 mutation• Aortic root ≥2 z score and systemic score ≥7• Ectopia lentis and FBN1 mutation known to beassociated with Marfan syndrome

• Positive family history of Marfan syndromeand ectopia lentis

• Positive family history of Marfan syndromeand systemic score ≥7

• Positive family history of Marfan syndromeand aortic root ≥3 z score in those <20 y ofage or ≥2 z score in those >20 y of age

Diagnosis of potential Marfan syndrome• FBN1 mutation with aortic root with a z score<3 in those <20 y of age

TABLE 2 Systemic Scoring System for theRevised Ghent Diagnostic Criteriafor Marfan Syndrome (Shown inTable 1)

Feature Value

Wrist and thumb sign 3Wrist or thumb sign 1Pectus carinatum 2Pectus excavatum or chest asymmetry 1Hindfoot deformity (eg, valgus) 2Pes planus 1Pneumothorax 2Dural ectasia 2Protrusio acetabulae 2Reduced upper-to-lower segment ratio andincreased arm-span-to-height ratio

1

Scoliosis or thoracolumbar kyphosis 1Reduced elbow extension 1Craniofacial features: 3 of the following—dolichocephaly, downward-slantingpalpebral fissures, enophthalmos,retrognathia, and malar hypoplasia

1

Skin striae 1Myopia 1Mitral valve prolapse 1

Adapted from Loeys et al.3 Z score calculations are basedon Roman et al.38

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syndrome will develop pectus excava-tum, which is often perceived asa disturbing physical feature byteenagers.13 The pectus deformity canbe severe and, in extreme circum-stances, can interfere with pulmonaryfunctioning, warranting surgical in-tervention.14 Pectus excavatum mayalso have a detrimental effect oncardiac function, especially duringsubmaximal exercising15 and is oftenrepaired before cardiac surgery foraortic root replacement. Pectus de-formity is often present before 10years of age but may worsen during anadolescent growth spurt.

Scoliosis is seen in slightly more thanone-half of individuals with Marfansyndrome and can be mild to severe

as well as atypically progressive.16,17

Close monitoring by using theforward-bending test at yearly inter-vals and management by an ortho-pedist is preferred because surgicalstabilization of the spine may be re-quired.18 Bracing has a low successrate if the curves are greater than35° to 40° but may have some pre-ventive value for smaller curves.Those with spinal curvatures lessthan 30° have an excellent long-termprognosis. Marked progression isoften seen by those with spinal cur-vatures greater than 50°. The pro-gression of scoliosis can occur wellinto adulthood. Thoracic kyphosis isalso common and can be postural ora further complication of bony over-growth and ligamentous laxity (eg,

kyphoscoliosis). Postural educationand joint stabilization with corestrengthening may be of benefit butare unproven for the treatment ofscoliosis in this population. Untreatedspinal deformities can lead to chronicback pain and restrictive lung disease.Spinal deformity correction is moreprone to complications than in idio-pathic deformity and should be per-formed by those with some experiencein treating patients with Marfan syn-drome.19

The acetabulum of the hip can beabnormally deep (protrusio acetabuli)in some patients with Marfan syn-drome and can lead to pelvic or upperleg pain. Protrusio acetabuli is seencommonly in Marfan syndrome20;

TABLE 3 Differential Diagnoses: Syndromes With Overlapping Features of Marfan Syndrome

Syndrome Manifestations Genetic Etiology

Mitral valve prolapse syndrome Mitral valve prolapse; skeletal manifestations as seen in Marfansyndrome

FBN1(in some)

MASS phenotype Mitral valve prolapse; myopia; nonprogressive aortic dilation;nonspecific skin and skeletal features

FBN1

Familial ectopia lentis Eye and skeletal findings of Marfan syndrome FBN1(in some)Shprintzen-Goldberg syndrome Skeletal and cardiac findings of Marfan syndrome; craniosynostosis;

hypertelorism; proptosis; abdominal hernias; joint laxity;developmental delay/intellectual disability

FBN1(in some)

Weill-Marchesani syndrome (autosomal dominant form) Ectopia lentis; short stature; brachydactyly; characteristic facialfeatures

FBN1

Loeys-Dietz syndrome Skeletal and cardiovascular features of Marfan syndrome; no ectopialentis; aggressive dilation of large- and medium-sized arteries; mostcommon and unique features include hypertelorism, bifid uvula/cleftpalate, blue sclerae, developmental delays, hydrocephalus,translucent skin, arterial tortuosity, and craniosynostosis

TGFBR1TGFBR2

Congenital contractural arachnodactyly Marfan-like skeletal features; “crumpled” ears; contractures of theknees, ankles, and digits at birth; progressive kyphoscoliosis;arachnodactyly; cardiac valvular anomalies

FBN2

Familial thoracic aortic aneurysm Dilation of the aorta and dissections either at the level of the sinuses ofValsalva or the ascending thoracic aorta without the other phenotypicfeatures of Marfan syndrome

Heterogeneous

Ehlers-Danlos syndrome, vascular type Thin skin with visible veins; easy bruising; small joint laxity; rupture ofhollow organs as well as medium- and large-size arteries

COL3A1COL3A2

Ehlers-Danlos syndrome, kyphoscoliotic form (type VI) Marfanoid body habitus; kyphoscoliosis; joint laxity; mitral valveprolapse; hypotonia; blue sclerae; ocular fragility; at risk for ruptureof medium-sized arteries

PLODZNF469

Homocystinuria Ectopia lentis; skeletal abnormalities such as those seen in Marfansyndrome; variable cognitive impairment; tendency for thromboticevents

CBS

Stickler syndrome Severe myopia; retinal detachment; hearing loss; midface hypoplasia;cleft palate; spondyloepiphyseal dysplasia

COL2A1COL11A1COL11A2COL9A1

Fragile X syndrome Often tall; long face; joint laxity; mild dilation of the aorta; mitral valveprolapse; pectus excavatum; variable intellectual disability

FMR1

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however, it is not unique to this con-dition and is seen in a number ofinfectious, inflammatory, metabolic, ge-netic, neoplastic, and traumatic con-ditions.21 In Marfan syndrome, theprotrusio acetabuli is often asymptom-atic, and surgical intervention is rarelyindicated.22

Some people with Marfan syndromewill show reduced mobility of the el-bow, but other joints may demon-strate ligamentous laxity. Joint laxitymay be more significant in youngpatients but rarely leads to motordelays. True joint dislocations arerare. Joint laxity can lead to muscle

fatigue and overuse pain/injury.23 Moretypically, such individuals demonstratepoor writing skills and complain ofhand pain/fatigue with prolonged use.Physical and/or occupational therapycan address these joint laxity issues byusing joint stabilization exercises, pos-tural support, education, alternative

FIGURE 1Growth curves for males in Marfan syndrome. (A) 50th percentile and (B) 95th percentile for the general population used for comparison. Reprintedwith permission from Erkula G, Jones KB, Sponseller PD, Dietz HC, Pyeritz RE. Growth and maturation in Marfan syndrome. Am J Med Genet. 2002;109(2):103.9

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strategies (eg, use of a laptop fortaking notes), and bracing/resting splintsif necessary.

Inward rotation of the medial aspectof the ankle can result in pes planus(Fig 5). This condition may lead tofoot, ankle, knee, hip, and/or low backpain.24 Some patients will benefit from

the use of shoe orthoses, such as anarch support and more supportiveshoes. Surgical intervention is rarelyindicated or fully successful. Otherswill have highly arched feet but havelittle or no symptoms.

The facial features of Marfan syndromeinclude a long and narrow face with

deeply set eyes (enophthalmos),downward slanting of the eyes, flatcheek bones (malar hypoplasia), anda small chin (micrognathia) (Fig 6).However, facial features are oftenhighly variable and may change withage. In addition, these facial featuresare not highly sensitive for the

FIGURE 2Growth curves for females in Marfan syndrome. (A) 50th percentile and (B) 95th percentile for the general population used for comparison. Reprintedwith permission from Erkula G, Jones KB, Sponseller PD, Dietz HC, Pyeritz RE. Growth and maturation in Marfan syndrome. Am J Med Genet. 2002;109(2):104.9

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presence of Marfan syndrome.25 Thepalate is often highly arched and nar-rowed (Fig 7).

Decreased bone density has beendocumented in the lumbar and hipregions in patients with Marfan syn-

drome.26,27 The etiology of this boneloss remains speculative, but no sig-nificant increase in bone fracturerates has been seen.28

OCULAR

Myopia is the most common ocularfeature and often progresses rapidlyduring childhood.29 Displacement ofthe lens (ectopia lentis) is a hallmarkfeature of Marfan syndrome but isonly seen in 1 or both eyes in ap-proximately 60% of affected individu-als.30 It is often the presenting featureand occurs much more commonlybefore 10 years of age. This finding ismost reliably diagnosed according toa slit-lamp examination after full pu-pillary dilation.

The globe is often elongated, and thecornea may be flat or even cone-shaped (keratoconus). People withMarfan syndrome are at increasedrisk of retinal detachment, glaucoma,and early cataract formation, typicallyin adulthood. Flashes of light (pho-topsia) and new floaters are symptomsof posterior vitreous detachment,which may precede retinal detach-ment.31,32 Retinal detachment shouldbe considered in any patient withacute onset of visual symptoms, andthese patients should be evaluatedand treated emergently. Most retinaldetachments can be repaired suc-cessfully, but the key to optimum vi-sual recovery is prompt diagnosis andtreatment.

Affected individuals should be followedup closely by an ophthalmologist fa-miliar with Marfan syndrome at leastyearly with slit lamp examinations forlens subluxation and evaluations forglaucoma and cataracts. Most often,eye problems can be controlled ade-quately with corrective lenses alone.Careful and aggressive refraction andvisual correction are mandatory inyoung children at risk for amblyopia.Lens dislocation can present a clinical

FIGURE 3Normative upper-to-lower segment ratios for (A) white and (B) African-American subjects. Reprintedwith permission from McKusick VA. Heritable Disorders of Connective Tissue. Philadelphia, PA: Mosby;1972.

FIGURE 4(A) Positive thumb sign with the thumbnail extending past the ulnar side of the hand and (B) positivewrist sign with the overlap of the nail beds of the thumb and fifth finger.

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challenge. Typically, the lens will subluxsuperiorly with Marfan syndrome. Ifthe lens is subluxed but still within thevisual axis, substantial lenticularastigmatism may result, which canrequire powerful astigmatic spectaclecorrection. If the lens edge has sub-luxed at or beyond the center of thevisual axis, aphakic spectacle or con-tact lens correction may improve vi-sion. If there is sufficient opticaldistortion from lens subluxation, sur-gical removal of the lens (aphakia) orlens replacement (pseudophakia) maybe the treatment of choice.33 Becauseof inherently weak zonular supportfor the Marfan lens, pseudophakiamay require supplemental means ofattachment to affix the intraocular

lens. Although this procedure is cur-rently considered safe when per-formed in specialized centers, majorcomplications, including retinal de-tachment, can occur. The long-termstability and safety of sew-in in-traocular lenses are unknown. Zon-ular weakness in Marfan syndromemay also result in complete lenssubluxation into the vitreous or resultin prolapse of the lens into the ante-rior chamber of the eye, which maynecessitate surgical removal. Cornealrefractive surgery for myopia is gen-erally contraindicated in individualswith Marfan syndrome, given the riskof additional eye complications.

CARDIOVASCULAR

The cardiovascular system is the ma-jor source of morbidity and mortalityin Marfan syndrome. Cardiovascularmanifestations include dilation of theaorta, aortic valve insufficiency, a pre-disposition for aortic tear and rupture,mitral valve prolapse with or withoutregurgitation, tricuspid valve prolapse,and enlargement of the proximal pul-monary artery.34

The aortic dilation in Marfan syndrometends to progress over time, with the

vast majority of cases becoming evi-dent before 18 years of age. The di-lation typically is at the level of thesinuses of Valsalva, but dilation of anypart of the aorta can be seen in thesepatients (Fig 8). Histologic examina-tion reveals elastic fiber fragmenta-tion with total loss of elastin contentand accumulation of amorphous ma-trix components in the aortic media.This “cystic medial necrosis” does notdistinguish Marfan syndrome fromother causes of aortic aneurysm and,therefore, is only a description, nota pathognomonic feature.

The age of onset and rate of pro-gression of aortic dilation are highlyvariable. As the aneurysm enlarges,the aortic annulus can be over-stretched, leading to secondary aorticregurgitation. Valvular dysfunction canlead to volume overload with second-ary left ventricular dilation and heartfailure. Indeed, mitral valve prolapsewith congestive heart failure is theleading cause of cardiovascular mor-bidity and mortality in young childrenwith Marfan syndrome.35

A significant risk of aortic dissectionor rupture occurs when the maximalaortic dimension reaches approximately

TABLE 4 Anticipatory Guidance in Marfan Syndrome

Option At Diagnosis 0–12 mo 1–5 y 6–12 ya 13–18 ya 19–22 y

Cardiac examinationb √ Each visit Each visit Each visit Yearly YearlyEchocardiogram √ As indicated Yearly Yearly Yearly Yearly

Ocular (ophthalmology) √ Yearly Yearly Yearly YearlyMusculoskeletalb

Scoliosis clinical examination √ Each visit Yearly Every 6 mo Every 6 mo YearlyJoint laxity √ Each visit Yearly Every 6 mo Every 6 moPectus deformity √ Each visit Yearly Every 6 mo Every 6 moBone age √c

Review diagnosis √ PRN PRN PRNd PRNd PRNd

Examine family members √ PRN PRN PRN PRN PRNSupport group information √ PRN PRN PRN PRN PRNGenetic counseling √ √e √e

Lifestylef √ √ √Transition Discuss plans Begin transition

Many systems should be reviewed regularly at developmentally appropriate stages. PRN, as needed.a Periods of rapid growth require closer supervision.b If abnormal results on examination, refer for further evaluation. Follow-up evaluations as indicated.c Bone age determination in preadolescence. If large discrepancy between bone age and height age, hormonal therapy should be considered.d Review symptoms of potential catastrophic events such as aortic dissection, vision changes, and pneumothorax.e Discuss reproductive and pregnancy risks.f Review physical activity restrictions/lifestyle modifications.

FIGURE 5Elongated feet with collapse of the medial archresulting in pes planus.

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5.0 cm in adults, although rupture at4.5 cm has been documented amongwomen.36 Fortunately, aortic dissectionis exceedingly rare in early child-hood. Acute aortic dissection usuallypresents as severe chest pain butcan also include pallor, pulselessness,

paresthesia, and paralysis. Asymmet-ric blood pressure may also be a signof dissection.

All individuals with a diagnosis ofMarfan syndrome should be followedup by a cardiologist familiar withMarfan syndrome. An echocardiogramshould be obtained at diagnosis. Asubsequent echocardiogram is oftendesired in 6 months to assess the rateof progression.37 Yearly echocardio-grams are sufficient when aorticdimensions are small (<4.5 cm inadults) and rates of aortic dilation arelow (<0.5 cm per year). Aortic rootmeasurements should be interpretedon the basis of normal values for ageand body size.38 Nomograms areavailable through the National MarfanFoundation (http://www.marfan.org/marfan/2576/Aortic-Root-Dilatation-Nomogram). More frequent evalua-tions are indicated when the aorticroot diameter exceeds 4.5 cm in adults,when the rate of aortic dilation exceeds

0.5 cm per year, or with the onsetof significant valvular or ventriculardysfunction. Aortic root dimensionscan also be determined by using com-puted tomography angiography ormagnetic resonance angiography, andthey potentially have the benefit ofevaluating beyond the aortic root.Because aortic dilation can occur atany age, lifelong monitoring is war-ranted.

Medications that reduce hemodynamicstress on the aortic wall, such asβ-blockers, are often prescribed.37

Therapy should be considered at thetime of diagnosis at any age or onappreciation of progressive aorticroot dilation, even in the absence ofa definitive diagnosis.39 The doseneeds to be titrated to effect, keepingheart rate after submaximal exerciseor agitation less than 110 beats perminute in young children or less than100 beats per minute in older childrenor adults. In patients who cannot

FIGURE 6Facial features of Marfan syndrome are highly variable, ranging from subtle findings to more “classic” facial features. Photo consents for publication onfile.

FIGURE 7High arched (“steepled”) palate.

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tolerate β-blockers (eg, individualswith asthma, depression, fatigue), ve-rapamil is commonly used,40 althoughrecently, concerns have been raisedabout calcium channel blockers andan increased risk of aortic complica-tions.41 Currently, randomized con-trolled trials are underway evaluatingthe response to the angiotensin re-ceptor blocker losartan, in responseto earlier mouse model work42 anda small cohort study.43 If congestiveheart failure is present as a result ofvalvular dysfunction, afterload-reducingagents (in combination with a β-blocker)

can improve cardiovascular func-tion, but surgical intervention maybe warranted.

Surgical repair of the aorta is in-dicated once: (1) the maximal aorticroot measurement exceeds 5.0 cm; (2)the rate of increase of the aortic di-ameter approaches 1.0 cm per year; or(3) there is progressive aortic re-gurgitation.44 More aggressive ther-apy may be indicated in individualswith a family history of early aorticdissection. Many individuals can re-ceive a valve-sparing procedure thatprecludes the need for chronic anti-coagulation therapy.45,46 Children runthe highest risk of requiring repeatedcardiac operations, such as valve re-placement.47

Aortic dilation can also be seen in thedescending aorta, although typically atlater ages. All people with Marfan syn-drome should begin intermittent sur-veillance of the entire aorta withcomputed tomography angiography ormagnetic resonance angiography scansin young adulthood.48,49 Such imagingshould also be performed at least an-nually in anyone with a history of aorticroot replacement or dissection.

Participation in contact sports, com-petitive sports, and isometric exercise

should be restricted.50 However, allpeople with Marfan syndrome can andshould remain active, with aerobicactivities performed in moderation.

Agents that stimulate the cardiovas-cular system, including routine use ofdecongestants, should be avoided.Caffeine can aggravate a tendency forarrhythmia. The use of psychostimu-lant medications for chronic fatigue orattention-deficit/hyperactivity disordershould be used with caution and beapproved by the cardiologist.

Subacute bacterial endocarditis pro-phylaxis may be indicated for dentalwork or other procedures expected tocontaminate the bloodstream withbacteria in the presence of significantvalvular insufficiency. With propermanagement, the life expectancy ofsomeone with Marfan syndromeapproximates that of the generalpopulation.51,52

PULMONARY AIRWAY

Pulmonary issues encountered inMarfan syndrome include spontane-ous pneumothorax, reduced pulmo-nary reserve, and sleep apnea. Inneonatal Marfan syndrome, an em-physematous lung disease is uniformlypresent and also occurs in approxi-mately 10% to 15% of those with“classic” Marfan syndrome.

Lung bullae, which develop in 4% to15% of patients with Marfan syndrome,can develop anywhere on the surfaceof the lungs but especially in the upperlobes.53 Such bullae (or blebs) canpredispose to spontaneous pneumo-thorax. Symptoms of pneumothoraxinclude sudden onset of chest pain,dyspnea, and/or cyanosis. Breathingagainst resistance (eg, playing abrass instrument), scuba diving, orhigh-altitude sports (eg, skydiving,mountaineering) should be avoided,especially among those with a familyhistory of spontaneous pneumothorax.Those with recurrent pneumothorax

FIGURE 8Dilation at the level of the aortic root as seen inMarfan syndrome. 1, aortic valve annulus; 2,aortic root (sinuses of Valsalva); 3, sinotubularjunction; 4, ascending aorta; AO, aorta; LA, leftatrium; LV, left ventricle. Rights to be retained byauthor (B.T.T.).

FIGURE 9Dural ectasia of the lumbar spinal canal. MRI appearance of the dilated dural sac, which can erode thebone and entrap nerves.

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may require chemical or surgicalpleurodesis or surgical resection ofpulmonary blebs.

A restrictive lung disease pattern withincreased total and residual lung vol-ume as well as exercise intolerance istypically seen in the majority of thoseaffected.54 Often, this pattern is re-lated to pectus deformity, chest wallasymmetry, and/or scoliosis. Surgicalrepair of severe pectus excavatum orscoliosis may improve overall pulmo-nary lung function. Pulmonary func-tion tests should be performed in anypatient with pulmonary complaints orsignificant pectus deformity and canbe monitored after surgical repair.

Obstructive sleep apnea is commonlyseen in patients with Marfan syn-drome.55 Increased nasal resistanceattributable to craniofacial abnormal-ities, such as a high arched palate,micrognathia with possible glossop-tosis, and laryngotracheomalacia, cancause difficulty with intubation/anesthesia as well as significant up-per airway resistance.56 Sleep apneais underappreciated among adoles-cents and young adults with Marfansyndrome. Symptoms commonly seenin Marfan syndrome that may bepartially attributable to sleep apneainclude fatigue and loss of energy aswell as impaired memory and cogni-tion. Symptoms of sleep dysfunction,such as fatigue, decreased sleep du-ration, nonrestorative sleep, andsnoring, should be reviewed at eachvisit. A formal sleep evaluation shouldbe considered in such cases.

INTEGUMENT

Approximately two-thirds of peoplewith Marfan syndrome develop stretchmarks of the skin.57 Often, these arelocated across the lower back as wellas the inguinal and axillary regions.These stretch marks are signs ofrapid growth and are usually per-pendicular to the axes of growth.

Because of the defect in connectivetissue, individuals with Marfan syn-drome are also at risk for hernias.Many will have inguinal herniation thatwill require surgical repair. However,recurrent hernias or hernias at thesite of surgical incisions are a moredistinctive hallmark of a connectivetissue disorder, such as Marfan syn-drome. Primary hernia repair shoulduse a synthetic mesh (or similar ar-tificial construct) in all known orsuspected cases of Marfan syndrometo minimize the risk of recurrence.

DURAL ECTASIA

Most individuals with Marfan syn-drome often develop stretching of thedural sac in the dependent lumbosa-cral region, resulting in dural ectasia(Fig 9).58 This development can lead tobony erosion and nerve entrapment.Symptoms can include pain in thelower back, hip/pelvic region, andproximal leg, as well as weakness/numbness above and below theknees.59 However, in most patients,the dural ectasia is asymptomatic.60

Excessive accumulation or leakage ofcerebrospinal fluid from the dural saccan cause postural hypotension and“low-pressure” headaches.61,62 Dam-age of the dura from spinal taps orepidurals may not sufficiently heal,causing leakage, which also predis-poses the patient to postural head-aches. In severe cases of dural ectasia,spinal shunting and/or medication canbe used. Complications after surgicalrepair of the dura include cerebrospinalfluid leakage and recurrence. Detectionof dural ectasia can be performed usingeither MRI or computed tomographyscan.

DENTAL

People with Marfan syndrome typicallyhave oromaxillofacial anomalies. Mosthave an elongated face, malar hypoplasia,high-arched palate, and micrognathia.

Often, these anomalies will cause sig-nificant dental crowding andmalalignment.Routine dental care is recommended;however, many individuals with Mar-fan syndrome require orthodontia forproper occlusion as well as appear-ance. Oral and maxillofacial interven-tions may also be indicated, such aspalatal expansion and/or mandibulardistraction.

PHYSICAL ACTIVITY

Although all children are encouragedto participate in physical activity foroverall health, skill development, co-ordination, musculoskeletal health,and socialization, individuals withMarfan syndrome are at significantrisk of physical injury and medicalcomplications. Of concern are activi-ties including contact sports and ac-tivities involving “burst” exertion (eg,sprinting) and intense static (iso-metric) exertion, such as weight lift-ing.63 In general, patients with Marfansyndrome without aortic dilation orsignificant mitral valve regurgitationare encouraged to participate incompetitive and noncompetitive (rec-reational) activities, but this action isstill limited by the intensity level of theactivity and the individual.50 Sports inwhich ocular trauma is likely, such asboxing or full-contact karate, shouldbe discouraged. Participation in anyactivity should be evaluated and dis-cussed before initiation of that activ-ity. Activities of most concern includebasketball, body building/weight lift-ing, hockey, running, skiing, racquet-ball, surfing, scuba diving, and rockclimbing. More acceptable alter-natives include modest hiking, sta-tionary cycling, bowling, golf, skating,snorkeling, and brisk walking. Cautionis needed for patients with low bloodpressure and orthostatic intolerance,including those receiving β-blockertherapy, who may be more susceptibleto easy fatigue, near-syncopal/syncopalepisodes, and falls.12

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PSYCHOSOCIAL

Marfan syndrome affects each in-dividual differently. Marfan syndromehas a significant effect on daily activ-ities and perceived quality of life.However, in 2 small series, most af-fected individuals older than 13 yearsreported a positive general self-im-age.64,65

Many of those affected by Marfansyndrome benefit from networkingand peer relationships. The NationalMarfan Foundation (www.marfan.org)is an excellent US resource for con-nections as well as medical advice.Most countries have similar organ-izations.

TRANSITION/MEDICAL HOME

Because Marfan syndrome can affectthe very young and continuesthroughout a patient’s lifetime, it isimportant that people with Marfansyndrome be recognized and havea medical home. Affected people areoften followed up by cardiologists,ophthalmologists, and orthopedists.66

Care needs to be coordinated amongthe various specialties, with a specialfocus on the period of transition fromadolescence to adulthood.

PREGNANCY

Pregnancy can lead to significantmedical complications for women withMarfan syndrome and should beapproached with careful delibera-tion.67 If the aortic root is exceeds 4.0cm, complications can include rapidprogression of aortic root enlargementand/or aortic dissection or ruptureduring pregnancy, delivery, and in thepostpartum period. Women whoseaorta is greater than 4.5 cm or whopreviously had an aortic dissection/rupture are at substantially higherrisk.68 Women with aortic dimensionsgreater than 5.0 cm are at significantrisk for aortic rupture, and pregnancy

should be delayed if possible until afterdefinitive treatment of the aorta hasbeen completed. If already pregnant,consideration of immediate aortic re-placement, early delivery, or terminationof the pregnancy should be consid-ered, given the potentially severeconsequences.

A higher-than-expected rate of spon-taneous abortion has been reportedin women with Marfan syndrome,although the etiology is unknown.69 Inaddition, women with Marfan syn-drome experience a higher rate ofpreterm deliveries, premature rup-ture of membranes, and increasedmortality of their offspring.69,70 Duralectasia should be considered in anyaffected individual, and avoidance ofspinal anesthesia may be necessary.Epidural anesthesia is safe for mostwomen with Marfan syndrome, al-though it is not advised for thosewith moderately severe dural ecta-sia. General anesthesia has the ben-efit of avoiding complication of spinalanesthesia with dural ectasia andless stress on the aorta during de-livery. Optimally, pregnancy shouldbe considered after appropriate coun-seling from a geneticist or a cardiolo-gist familiar with Marfan syndrome,a genetic counselor, and a perinatol-ogist.

PRENATAL

The pediatrician is sometimes calledon to counsel a family prenatally withregard to Marfan syndrome. The pe-diatrician may have been previouslyinvolved with this family through careof siblings or one of the expectantparents. Families may also seek pe-diatric advice in the care and man-agement of a fetus at risk. Thismanagement may involve a few dif-ferent scenarios.

1. The pediatrician may be askedabout the risk to a child of a parentwith Marfan syndrome. The risk of

inheriting the genetic defect inMarfan syndrome is 50%, consis-tent with autosomal dominant in-heritance. Often, expectant parentsare concerned about the severityof the disorder in the next genera-tion. Variability of the Marfan phe-notype is extensive but is moresimilar among affected familymembers, suggesting that the ge-netic defect is largely responsiblefor the phenotype. Most peoplewith classic Marfan syndrome donot have children with a muchmore severe phenotype, such asneonatal Marfan syndrome.71 Oneshould also be aware of the conse-quences that may affect the preg-nancy outcome for women withMarfan syndrome. As mentionedpreviously, women with an aorticroot greater than 4.5 cm in diame-ter should avoid pregnancy or un-dergo elective aortic graftingbefore becoming pregnant.72 Aorticdissection or rupture has occurredin women with an aorta less than5.0 cm, which may result in signif-icant morbidity and mortality ofthe fetus/infant and the expectantmother.

2. Parents of a child with Marfan syn-drome may ask about recurrencerisk of Marfan syndrome in subse-quent pregnancies. This issue maybest be explained by a geneticist. Inshort, 1 of the parents may eitherbe unrecognized as having Marfansyndrome (therefore, recurrencerisk is 50%) or both parents maybe unaffected and, therefore, carryonly a slight chance of having a lowlevel of germline mosaicism (withanticipated recurrence risk of 2%–3%). Because of a high occurrenceof unrecognized Marfan syndromein parents of a child with Marfansyndrome, it is advisable for bothparents to undergo further evalua-tion to establish their own personal

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risk as well as the risk for subse-quent pregnancies.

3. An expectant couple may have a fe-tus with concerning features of neo-natal Marfan syndrome discoveredthrough prenatal ultrasonographyor even fetal MRI. Ultrasonographicfindings may include unusually longlimbs and congenital heart diseaseand are often detected in the thirdtrimester.73 Genetic testing for FBN1mutations by using amniocentesismay be helpful to confirm the diag-nosis of Marfan syndrome and toreveal specific mutations in FBN1that may be more typically associ-ated with neonatal Marfan syn-drome and, therefore, reducedsurvivability.

NEONATAL MARFAN SYNDROME

Neonatal Marfan syndrome is the mostsevere disorder attributable to a fibril-linopathy. Features overlap significantlywith classic Marfan syndrome but aremore severe. Infants with neonatalMarfan syndrome are long with simple/crumpled ears, aged-appearing face,enlarged corneas, ectopia lentis, chestdeformity, large feet, arachnodactyly,and contractures.74 Respiratory insuf-ficiency is common as a result of anabnormally pliant chest wall and em-physematous changes in the lungs.

Cardiac abnormalities are severe andinclude polyvalvular dysplasia andaortic dilation. Mortality is high withinthe first year of life because of cardiacfailure secondary to severe mitralvalve regurgitation.75 Almost all casesof neonatal Marfan syndrome aresporadic and are associated withmutations clustering within exons 24through 32 of FBN1.

SUPPORT GROUPS

National Marfan Foundation22 Manhasset Ave,Port Washington, NY 11050Phone: 1-800-8-MARFAN ext 10(1-800-862-7326); 1-516-883-8712Fax: 1-516-883-8040E-mail: [email protected] site: www.marfan.orgCanadian Marfan AssociationCentre Plaza Postal Outlet128 Queen St SouthPO Box 42257Mississauga, ONT, L5M4Z0, CanadaPhone: 866-722-1722 (toll-free); 905-826-3223Fax: 905-826-2125E-mail: [email protected] site: www.marfan.caMarfan Association UKRochester House5 Aldershot RdFleet, Hampshire

GU51 3NG, EnglandPhone: (0) 1252 810472E-mail: [email protected] site: www.marfan.org.uk

LEAD AUTHORSBrad T. Tinkle, MD, PhDHoward M. Saal, MD

COMMITTEE ON GENETICS, 2011–2012Robert A. Saul, MD, ChairpersonStephen R. Braddock, MDEmily Chen, MD, PhDDebra L. Freedenberg, MDMarilyn C. Jones, MDJames M. Perrin, MDBeth Anne Tarini, MD

FORMER COMMITTEE ON GENETICSMEMBERSHoward M. Saal, MD, ContributorBrad T. Tinkle, MD, PhD

LIAISONSSara Copeland, MD — Maternal and ChildHealth Bureau/Health Resources and ServicesAdministrationKatrina M. Dipple, MD, PhD— American Collegeof Medical GeneticsW. Allen Hogge, MD — American Congress ofObstetricians and GynecologistsMelissa A. Parisi, MD, PhD — Eunice KennedyShriver National Institute of Child Health andHuman DevelopmentStuart K. Shapira, MD, PhD — Centers forDisease Control and Prevention

STAFFPaul Spire

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